High Throughput Screen for Small Molecule Probes for Neural Network Development

描述（由申请人提供）：许多主要的神经发育障碍，包括自闭症、癫痫和精神分裂症，被认为是由大脑发育过程中突触形成异常引起的，导致某些类型的突触过量或不足。我们的长期目标是了解中枢神经系统（CNS）突触形成的分子机制，以开发治疗这些毁灭性疾病的方法。突触形成的过程在周围神经系统中得到了最好的表征，其中有报道称，在多个单基因敲除小鼠中，神经肌肉连接完全丧失。在中枢神经系统中，尽管存在许多在体外表现出强突触形成活性的蛋白质，但其中一些蛋白质的遗传缺失只会导致突触密度的细微变化，仅限于少数神经元。这些结果表明中枢神经系统中的突触形成机制是严重冗余的；这种情况使得应用传统的遗传方法来研究这个问题效率低下。我们相信，对突触形成决定因素进行公正的化学筛选，具有阻断或增强关键途径和整个基因类别的潜力，可能为研究中枢神经系统中的突触形成机制提供更有效的方法。此外，该研究还可能产生小分子探针，用于干扰突触形成和体内兴奋-抑制平衡。特定突触的过剩或不足已经被假设为许多神经发育障碍的基础，但到目前为止，由于缺乏干扰潜在网络连接的工具，这些假设很难证明。我们相信我们的建议将纠正这种情况，同时产生一个高影响力的数据集，将阐明中枢神经系统突触形成的机制。

DESCRIPTION (provided by applicant): Many major neurodevelopmental disorders, including autism, epilepsy and schizophrenia, are believed to the caused by aberrant synapse formation during brain development, resulting in an excess or deficit of certain classes of synapses. Our long term goal is to understand the molecular mechanisms of synapse formation in the central nervous system (CNS), with the aim of developing therapeutics for these devastating diseases. The process of synapse formation has been best characterized in the peripheral nervous system, where the complete loss of neuromuscular junctions has been reported for multiple single gene knockout mice. In the central nervous system, despite the presence of many proteins that show strong synaptogenic activity in vitro, genetic deletion of several of these proteins result in only subtle changes in synapse density limited to small populations of neurons. These results suggest that the synaptogenic machinery in the CNS is heavily redundant; a situation that makes it inefficient to apply traditional genetic approaches to study the problem. We believe that an unbiased chemical screen for determinants of synapse formation, with its potential to block or enhance key pathways and entire classes of genes, may present a more efficient approach to studying synaptogenic mechanisms in the CNS. In addition, the study may also generate small molecule probes that will be useful in perturbing synapse formation and excitatory-inhibitory balance in vivo. An excess or deficit of specific synapses has been hypothesized to underlie many neurodevelopmental disorders, but to date, these hypotheses have been difficult to prove due to the lack of tools to perturb the underlying network connectivity. We believe our proposal will remedy this situation, and at the same time generate a high impact dataset which will shed light on the mechanisms of synapse formation in the CNS. PUBLIC HEALTH RELEVANCE: Defects in brain development leading to an excess or deficit of synapses may result in neurodevelopmental disorders such as autism, schizophrenia, epilepsy and mental retardation. Currently, no drug exists to directly target the development of synapses in the brain. We propose to screen a large chemical library for compounds that will modulate synapse development in the intact brain, and thereby shed light on the molecular mechanisms of the process as well as provide candidate compounds for both investigative and therapeutic purposes.